SUMMARY Central cholinergic signaling is implicated in attention, learning and memory processes. Despite substantial progress in understanding molecular and cellular aspects of the function of acetylcholine receptors in the central nervous system, significantly less is progress has been made at relating the functions of ACh at the cellular level with the effects of ACh on cognition. The research program supported by NS22061 is dedicated to elucidating the contribution of nAChRs to CNS function and dysfunction. Our current goal is to quantitatively map the role of cholinergic signaling and nAChRs in establishing the activity footprint or ?engram? of emotionally salient memories. We propose to combine state-of-the art genetic tools for engram labeling with electrophysiological, pharmacological and optogenetic methods to address the role of ACh in modulating network function. Specifically we will test the hypothesis that ACh controls the magnitude and indelibility of emotionally salient memories encoded in the basal lateral amygdala; and further that there is a cholinergic engram in the basal forebrain that is associated with specific learning paradigms. Our rationale for posing this hypothesis stems from observations that neurons within the basal lateral amygdala (BLA) are critical for establishing emotionally salient memories. The BLA receives robust cholinergic input from the basal forebrain and we have demonstrated that this cholinergic input is critical for BLA dependent learning and memory, that endogenous ACh increases the excitability of BLA neurons and further that plasticity at cortical-amygdala synapses requires ACh and nicotinic ACh receptors (nAChRs). To test this hypothesis we will address three specific questions: How does endogenous ACh circuit activity affect the BLA fear memory engram? What is the contribution of nAChRs to the cholinergic modulation of the fear memory engram? Does long term nicotine exposure change the cholinergic and BLA fear engrams? If our hypothesis is correct, then one would predict that specific manipulations of nAChR cholinergic signaling could be exploited to adjust the potency and durability of emotionally salient memories. Such alterations could be clinically relevant for selective ablation of memories in individuals with stress- related memory disorders, such as patients with PTSD or for patients with anxiety-disorders. Likewise, these studies could help to better target new therapeutics for restoring positive memories in patients with neurodegenerative diseases resulting in memory loss, such as Alzheimer?s and Parkinson?s disease.